**1. Introduction**

Azoospermia (a-, without + –zoo– » Greek zôion, animal + –spermia– » Greek sperma, sperm/seed) is defined by the absence of sperm in the ejaculate. Although the term does not imply an underlying etiology, azoospermia inevitably provokes infertility [1]. According to global estimates, 1 out of 100 men at reproductive age and up to 10% of men with infertility are azoospermic [2–4].

Azoospermia is broadly classified into obstructive and nonobstructive. This differentiation is clinically meaningful because it affects patient managemen<sup>t</sup> and treatment outcomes [4]. Notably, nonobstructive azoospermia (NOA) relates to an intrinsic testicular defect caused by various conditions that ultimately affect sperm production profoundly.

The severe spermatogenic deficiency observed in NOA patients is often a consequence of primary testicular failure affecting mainly spermatogenic cells (spermatogenic failure (STF)) or related to a dysfunction of the hypothalamus-pituitary-gonadal axis (hypogonadotropic hypogonadism (HH)). From this point on, the acronyms STF and HH will distinguish these types of NOA, as appropriate [5]. The above-proposed terminology might be more intuitive for the clinician. It not only indicates the site of the problem (central or local) explicitly, but also makes it clear that the testicular disorder refers primarily to a spermatogenic defect, unlike the indistinct term 'testicular failure' that may relate to an isolated spermatogenic defect or such a defect combined with Leydig cell failure.

The differential diagnosis between STF and HH is also essential because the former is linked with severe and untreatable conditions, whereas the latter can be effectively treated with gonadotropin therapy [5,6]. By contrast, obstructive azoospermia (OA) originates from a mechanical block along the reproductive tract, namely, vas deferens, epididymis, or ejac-

**Citation:** Andrade, D.L.; Viana, M.C.; Esteves, S.C. Differential Diagnosis of Azoospermia in Men with Infertility. *J. Clin. Med.* **2021**, *10*, 3144. https:// doi.org/10.3390/jcm10143144

Academic Editors: Ettore Caroppo, Giovanni M. Colpi and Kent Doi

Received: 3 June 2021 Accepted: 13 July 2021 Published: 16 July 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

ulatory duct [7,8]. Unlike NOA, spermatogenesis is preserved, and both reconstructive procedures and sperm retrieval are typically highly successful in OA patients [7–10].

Nonobstructive azoospermia can be distinguished from OA using history, physical examination, semen analysis, hormonal assessment, and genetic testing in most patients [4,5,11]. However, in some instances, this distinction is not straightforward, and a testis biopsy is required. In this article, we first provide readers an overview of the azoospermia differential diagnosis. Secondly, we discuss the differential diagnosis in cases of doubt, including a workable clinical algorithm. Lastly, we present exemplary clinical cases to illustrate a difficult diagnosis and its outcomes.

#### **2. Azoospermia Differential Diagnosis: An Overview**

The primary goals of the differential diagnosis are the identification of:


It is critical to evaluate the azoospermic patient using a standardized workup to achieve these goals, as discussed in the next sections.
